This is a Research Scientist Award (RSA) for Dr. Allyn C. Howlett, whose academic experience includes a B.S. cum laude in Biochemistry from Pennsylvania State University, a Ph.D. in Pharmacology and Toxicology from Rutgers University, post-doctoral work with Alfred G. Gilman at the University of Virginia, and 20 years on the faculty at Saint Louis University School of Medicine. Dr. Howlett is a tenured Professor in the Department of Biology and Director of the Neuroscience/Drug Abuse Research Program at the Julius L. Chambers Biomedical/Biotechnology Research Institute at North Carolina Central University. Dr. Howlett's research effort is concentrated on the pharmacological, biochemical and cellular regulation of the CB1 receptor. Her intention is to maintain an active research laboratory in which students, fellows, and visiting scientists can exchange ideas and share expertise. Toward this goal, Dr. Howlett is seeking this RSA in order to allow ample research time to conduct her research, mentor students and fellows, and to maintain research collaborations. The RSA will also foster continued professional development through participation in research meetings and short courses, and communication with other research scientists. Dr. Howlett's research projects have been described by two NIDA-funded R01 grants. "Cannabinoid Receptor Structure-Activity Relationships" examines the receptor interactions with ligands of various chemical classes (cannabinoid, amincialkylindole, eicosanoid and arylpyrazole) in an effort to define the requirements for high affinity ligand-receptor association and efficacy. This project involves close collaboration with synthetic chemists and computational chemists. "Cannabinoid Receptors in Neuronal Cells and Brain" addresses the signaling mechanisms by which the CB1 receptor evokes its response through selected G protein subtypes and their ensuing signal transduction pathways [adenylyl cyclase, mitogen-activated protein kinase (MAPK) and other kinases, Ca2+ mobilization and nitricoxide synthase (NOS) activation]. The project also examines the mechanisms by which the cell regulates signal transduction through the reversible post-translational modifications of palmitoylation and phosphorylation.